title: Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336).
abstract: BACKGROUND
  Patients with metastatic colorectal cancer who progress on standard chemotherapy have limited treatment options. New and effective drugs are needed for these patients. Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xenograft models.
  
  
  METHODS
  Patients were required to have pathologically verified, measurable, metastatic or locally advanced colorectal cancer that was surgically unresectable. They must have failed either one or two prior chemotherapy regimens, had performance status of 0-1, adequate bone marrow, renal and hepatic function, and no significant cardiac disease. Patients were treated with romidepsin at a dose of 13 mg/m(2) as a 4-h iv infusion on days 1, 8, and 15 of a 28-day cycle. The study had a two stage design. The primary objective of the study was to determine the confirmed response probability in this group of patients treated with romidepsin.
  
  
  RESULTS
  Twenty-eight patients were registered to the study, two of whom were ineligible. One eligible patient refused all treatment and was not analyzed. For the 25 remaining patients, performance status was 0 in 16 patients and 1 in nine patients. Ten patients had received one prior chemotherapy regimen and fifteen 2 prior regimens. Out of the 25 eligible and analyzable patients accrued in the first stage of the protocol, no objective responses were observed and the study was permanently closed. Four patients had stable disease as the best response. Twenty-five patients were assessed for toxicity. No grade 4 or greater toxicities were seen. Fourteen of the 25 patients experienced grade 3 toxicities the most common of which were fatigue or anorexia.
  
  
  CONCLUSIONS
  Romidepsin at this dose and schedule is ineffective in the treatment of patients with metastatic colorectal cancer after prior chemotherapy. Future trials might evaluate combinations of romidepsin with chemotherapeutic or other agents.
authors.affiliation: Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 903 Clinical Science Building, MSC 635, Charleston, SC 29425-6350, USA. whiterp@musc.edu
authors.forename: Robert P
authors.initials: RP
authors.lastname: Whitehead
authors.forename: Cathryn
authors.initials: C
authors.lastname: Rankin
authors.forename: Paulo M G
authors.initials: PM
authors.lastname: Hoff
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Gold
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Billingsley
authors.forename: Robert A
authors.initials: RA
authors.lastname: Chapman
authors.forename: Lucas
authors.initials: L
authors.lastname: Wong
authors.forename: John H
authors.initials: JH
authors.lastname: Ward
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047630:Depsipeptides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; C087123:romidepsin